Primary cancer of the liver (hepatocellular tumor, hepatoma) is a disease with a dismal prognosis due to its relentless progression despite many therapeutic modalities. Although uncommon in the United States (approximately 14,000 new cases per year), hepatoma is the most prevalent tumor in the most populous countries of the world. It is quite common in sub-Sahara Africa, Southeast Asia, Japan, the Pacific Islands, Greece and Italy. For those patients not surgically resectable, media survival is approximately 8 weeks. In North America, this malignancy most commonly arises in elderly patients with alcoholic or postnecrotic cirrhosis. However, in other parts of the world, it is epidemic and often occurs in young patients. This demographic variation is correlated with a high incidence of early childhood infection with hepatitis B virus in the geographic areas where hepatocellular tumor is most common.
Although the incidence of primary liver cancer is not high in the United States, cancer of the colon is a major health problem, and cancer of the colon reaches the liver in about 50% of the patients. Over 140,000 new cases are diagnosed yearly. Once the disease has spread, therapy is ineffective, with approximately 50% of all patients dying from their disease within five years of diagnosis. In 15% to 20% of the patients, the tumor will have spread to the liver by the time of diagnosis, and in over 50% of patients, colon cancer will eventually spread to the liver metastasis even when there is no tumor spread elsewhere. Tumor cells reach the liver via the portal vein and establish a blood supply from the hepatic artery, perhaps through the elaboration of tumor anglogenesis factor(s).
The impact of colon cancer on the liver is grim. When liver metastases are diagnosed, the median survival time falls to 4-9 months without treatment. While tumors that originate in other organs do not spread to the liver as frequently, their prognosis is also significantly worsened when they reach the liver. Much medical research assumes that effective treatment of tumors in the liver will extend survival, improve quality of life, and reduce the financial and emotional impact of this disease.
It is a widely held view, and currently being acted upon, as noted below, that effectiveness of chemotherapy is improved by intraarterial infusion. However, systemic toxicity has limited drug tolerance. An effective means for detoxification of blood containing chemotherapeutic agents has not been developed until this invention.
The current treatment modalities for colon tumor metastatic to the liver are unsatisfactory. A solitary metastatic deposit of colon cancer is best handled by surgical resection, which leads to a 1 year survival rate of 80% and a 3-year survival rate of 40%. However, in 95% of the cases, multiple metastatic lesions are present. Systemic chemotherapy has little lasting effect on these metastatic lesions. Although certain drugs have shown activity in various studies, when used at higher doses their effects are negated by their systemic toxicities. These same drugs may prove to be much more effective if their systemic toxicities can be avoided. A treatment which exposes a tumor to high antineoplastic drug concentrations and removes the drug from the blood before systemic exposure occurs may be an effective therapy for cancer in the liver.
At present surgical resection offers the only chance of cure of hepatoma. For resection to be possible, at least one hepatic segment must be spare& The uninvolved segment(s) of liver must be free of cirrhosis. Unfortunately, the proportion of patients with potentially resectable tumors is small.
Hepatic artery infusion (HAI) of chemotherapy has been widely investigate& Arterial infusion of 5-FU and FUDR increases their effectiveness by delivering the drug directly to liver tumor cells before its dilution by the systemic circulation. This approach is attractive because hepatocellular tumors frequently remains localized to the liver, and, like most chemotherapeutic drugs, 5-FU displays a dose-response effect, i.e., increasing the dose can give a proportionately greater increase in effect. Also, certain drugs, including the fluorinated pyrimidines, doxorubicin and others, are metabolized by the liver and excreted through the biliary tract thereby reducing systemic drug toxicity.
Initially, chemotherapy was given via percutaneously placed catheters with the use of external pumps. Response rates obtained with this form of treatment in patients with colon cancer metastatic to the liver was generally superior than those attained when identical drugs were given intravenously, with objective responses seen in 34% to 83% of the patients. More recent studies, employing surgically placed catheters and implanted pumps, have yielded response rates in 50% to 60% (range 20% to 88%) of the patients with colon cancer metastatic to the liver. The fluorinated pyrimidines (5-FU and FUDR) are the drugs most commonly used for prolonged (over 1 to 2 weeks) HAI, while Mitomycin C and other drugs have been given alone or in combination with these drugs as intermittent bolus injections into the hepatic artery. To date, no randomized comparative studies have demonstrated that HAI administration of fluorinated pyrimidines is therapeutically superior to systemically administered drug. Local and systemic toxicities limit the mount of therapy which can be delivered even by the arterial route.
Local toxicities in the gastrointestinal tract have included gastric and duodenal ulceration, gastric bleeding and/or perforation, severe dyspepsia, gastritis and diarrhea Many of the patients who developed these local toxicities were found to have had a misplaced or dislodged catheter tip. In these cases, the drug was perfusing a large portion of the stomach and duodenum via the gastric arteries. Gastrointestinal toxicities did not occur when the gastric arteries were separated and ligated from the hepatic artery or embolized at the time of catheter placement. Diarrhea, a systemic toxicity of the fluorinated pyrimidines, occurs more commonly in patients with arterial to venous (A-V) shunting of 30% or greater. A-V shunting allows drug to bypass functioning liver cells and avoid being metabolized by the liver thereby increasing systemic drug exposure. FNT 1. Toxicity resulting from unintentional injection of drug into an artery other than a hepatic artery, most often gastric or duodenal branches.
Local hepatobiliary toxicities (hepatitis, cholecystitis, biliary sclerosis, stenosis and stricture) occur in up to 50% of the patients treated with conventional HAI5-FU or FUDR chemotherapy. The gallbladder and biliary tree receive all of their blood supply from the hepatic artery whereas the liver receives approximately one-fourth of its blood supply from the hepatic artery. Biliary tract toxicity seems to be more common in patients who have had the blood supply to the biliary tree disrupted by ligation of the gastric arteries. Choliangiography, CT scanning and alkaline phosphatase elevations have been shown to be effective monitoring tools for identifying patients with impending biliary tract toxicity. Hepatitis, manifested by nausea, vomiting, abdominal pain and jaundice in association with elevated serum concentrations of liver transarninases and billirubin has occurred in patients receiving conventional HAI 5-FU or FUDR. Hepatitis appears to be related to the dose and duration of the hepatic arterial drug infusion.
Systemic toxicity of HAI chemotherapy has not been a major problem when drugs with a high liver extraction ratio, such as 5-FU and FUDR, have been given in conventional doses that are defined by systemic toxicity. Drugs which are not substantially metabolized by the liver upon first pass often cause system toxicities, primarily myelosuppression, when given intraarterially. Obviously, without the use of a detoxifying system that removes unmetabolized drug, most drugs cannot be employed in higher, potentially more effective, doses by the HAI route.
Systemic chemotherapy for hepatocellular tumor remains a therapeutic challenge. Numerous agents have been tested in Phase II trials; objective responses to therapy are uncommon. 5-FU and doxorubicin (Adriamycin) are the only drugs which have consistently been shown to have significant activity. Initial reports of East African blacks treated with doxorubicin, 75 mg/m.sup.2 every 3 weeks, resulted in 22 patients attaining an objective response (3 complete) in 50 patients treated. Substantial toxicity occurred with the use of doxorubicin at this dose. Hence, most other studies report on the use of doxorubicin, 60 mg/m.sup.2 every 3 weeks. At this dose, objective therapeutic responses occurred in approximately 20% of the patients.
Ausman, R. K. (1961) Development of a technic for isolated perfusion of the liver, N.Y. State J. Med., vol. 61, p. 3993. discloses isolating the liver by surgically separating the portion of the inferior vena cava which includes the hepatic veins, infusing a chemotherapy agent to the liver through the splenic and common hepatic arteries, and collecting the chemotherapy agent from the isolated portion of the inferior vena cavil This reference does not disclose a method for detoxifying blood of chemotherapeutic agent.
K. Schwemmle and K. Aigner, Recent Results in Cancer Research, vol. 100, pp. 229-233, pub. by Springer-Verlag, Berlin, 1986, utilized isolated hepatic perfusion in two patients suffering from disseminated hepatic metastases of colorectal cancer. They characterize their work, and that carried out prior to their efforts, as follows:
"Among the various treatment modalities for liver metastases such as resection, intraarterial infusion, isolated perfusion, or chemoembolization, isolated perfusion enables chemotherapeutic agents to be added to the perfusion circuit in dosages higher than could be tolerated by systemic administration. The upper limit of dosage is only the local toxicity. Because hepatic metastases are mainly vascularized by the hepatic artery, intraarterial infusion of anti-cancer agents provides a much higher concentration of the drug in these tumors than can be achieved by systemic chemotherapy. PA0 "To develop a method for intraarterial treatment with maximal doses of chemotherapeutic drugs, we started with isolated perfusion of the liver in animal experiments according to previously published methods [4-6]. Optimal surgical techniques and drug toxicity were studied in dogs. After these studies in animals had proved that the method was practicable and safe, in November 1981 we performed an isolated hepatic perfusion in two patients suffering from disseminated hepatic metastases of colorectal cancer [1]. After these two patients had survived 5 months without complication, another 38 patients were submitted to isolated hyperthermic perfusion of the liver with chemotherapeutics [2]. PA0 "In the isolated perfusion circuit both the hepatic artery and portal vein are perfused and the hepatic venous return is collected via a single venous line. During isolated perfusion a portocaval shunt is established in which ammonium is filtered out of the portal blood (FIG. 1). Recently, we have omitted the filtration unit. PA0 "During the operative procedure through an abdominal midline incision the liver, the hepatoduodenal ligament, and the inferior caval vein are exposed. Tourniquets are placed around the gastroduodenal arterial and portal vein and around the caval vein below and above the renal veins as well as intrapericardiall. PA0 "In order to collect the hepatic venous outflow a double-channel catheter is inserted into the caval vein from below the renal veins. This special catheter consists of a longer channel shunting the caval vein to maintain cardiac venous return and a second shorter channel for the isolated hepatic venous return. The portocaval shunt tube is inserted into the caval vein channel, whereas two lateral openings collect the venous return from the kidneys. PA0 "After the perfusion catheter is inserted into the caval vein the portal vein is cannulated in both directions. The peripheral catheter is connected to the portocaval filtration unit consisting of a roller pump and a hemofiltrating system. At flow rates of approximately 300-400 ml portal venous blood has been filtered and with adequate volume substitution returned to the caval shunt tube. Thus blood levels of ammonium have been kept within normal ranges during the period of isolated hepatic perfusion. In case of leakage to the systemic circulation a part of the anti-cancer drugs as well has been filtered out in that portacaval shunt. As soon as the shunt is established, the common hepatic artery is clamped and perfusion is started via the central portal veto catheter in a partial circuit. Then the arterial catheter is inserted into the gastroduodenal artery and the liver is perfused via two arterial lines at a low rate of 200-350 ml/min in the hepatic artery and 150 ml/min in the portal vein. Heating the perfusion circuit the temperature of the hepatic tissue is increased. The temperature, which should not exceed 40.degree. C., is measured with needle probes in the right and left liver lobes. In our first 31 isolated liver perfusions we only applied 5-fluorouracil (5-FU) in a dosage between 500 and 1000 mg. In the last eight patients a combination consisting of mitomycin C and 5-FU was used. PA0 "Few complications occurred after isolated liver perfusion. Three patients died a short time after the operation. One patient died 2 hours later from untreatable bleeding after an isolated hepatic perfusion combined with a hemihepatectomy. The tumor had already infiltrated the caval vein. In another patient septicemia and respiratory distress occurred 6 days after the perfusion. The third patient died from renal failure 2 weeks after the perfusion. His autopsy showed a 90% regression of the tumor. Seventy percent of the hepatic tissue in this case had been involved in metastases. In the last 30 patients there were no fatal outcomes. PA0 "In spite of the increased survival time unfortunately in the combined group the patients developed extrahepatic metastases after the treatment. In ten cases (83%) metastases of the lung developed. Half of the patients developed peritoneal carcinosis or at least positive lymph nodes at the hepatoduodenal ligament and in three cases (25%) recurrences at the colorectal anastomoses or at the perineal scar developed." PA0 "In conclusion we see the following advantages of liver perfusion: PA0 "The most important disadvantage of this method is the fact that the perfusion cannot be repeated. However, it is possible at any time to continue the therapy with intraarterial infusions and/or with chemoembolization." PA0 "Chemotherapy of cancer has not been entirely satisfactory because the administration of doses large enough to significantly affect a tumor produce serious toxic effects on the bone marrow and gastrointestinal tract." FNT 3. Surgery--Gynecology Obstetrics, vol. 120, no. 6, pp. 1187-1193 (June, 1965) FNT 4. JSR, vol 1, no. 2, pp. 111-116 (July, 1961) (deals specifically with liver isolation) Pierpont, et al..sup.5, and Shingleton, et al..sup.6 None discloses detoxifying blood which has passed through an isolated organ and returning the detoxified blood to the patient. PA0 "Techniques for perfusion of the liver have been complicated, and represent major abdominal surgery. Our techniques, developed for the experimental animal and applicable to patients, involved isolation of the liver by passing a Foley balloon catheter (Bard Urological Division, Murray Hill, N.J.) with a ligated tip through the vena cava from the femoral vein to a point proximal to the hepatic veins. The vena cava was occluded above by the balloon that was positioned above the diaphragm and below the hepatic veins by a snare placed above the renal veins (FIG. 7), and the hepatic vein drainage was returned to the pump reservoir through the catheter. The hepatic artery was temporarily clamped, and oxygenated blood, and oxygenated blood from the pump and the chemotherapeutic agents were delivered to the liver through the proximal portal vein. Blood from the distal portal vein and vena cava was returned to the heart through an accessory bypass from the femoral vein to the external jugular vein. We did not persist in our efforts to use hepatic perfusion clinically, but other investigators have separately developed techniques for perfusion of human livers. The approach developed by Aigner and colleagues uses a double-lumen tube to collect hepatic venous blood in the outer tube, with bypass of the distal caval blood through the inner tube. Arterial blood and chemotherapy are FNT 5. J. Thoracic and Cardiovas. Surg., vol 39, no. 2. pp. 159-165 (February, 1960) FNT 6. Annals of Surgery. vol 152, no. 4, pp. 583-593 (October, 1960) FNT 7. The Journal of Urology, vol 131, pp. 36-40 (1984) and Investigative Urology, vol. 19, No. 3, pp. 176-178 FNT 8. Said to have utilized "selective delivery of the anticancer drug is achieved by percutaneous injection of 1 mg/kg of mitomycin C into a drug-chamber of an operatively implanted vascular access port, another end of which is inserted in the feeding artery of the cancer-bearing organ." PA0 "Removal of the drug is performed by the usual method of charcoal hemoperfusion," Dr. Agishi stated. "However, in order to augment the anticancer effect, local hyperthermia is established utilizing a radiofrequency wave--13.56 MHz--emission apparatus." (Miles Pharmaceutical Oncology News Update, 1987) delivered through the hepatic artery and proximal protal [sic: portal] vein to the liver. This method is under study, particularly in Germany, and has been performed safely with acceptable morbidity." PA0 Weik, et al., U.S. Pat. No. 4,573,966, patented Mar. 4, 1986, and U.S. Pat. No. 4,610,662, patented Sep. 9, 1986, describe the use of double balloon catheters to treat stenosis; PA0 Solar, U.S. Pat. No. 4,546,759, patented Oct. 15, 1985, is directed to a triple balloon catheter to assist right ventricle functioning;, PA0 Hussein, et al., U.S. Pat. No. 4,445,892, patented May 1, 1984, relate to a dual balloon catheter for insertion in blood vessels to provide an isolated operating region in the vessel between the balloons which facilitates the use of an optic system; PA0 Baran, et al., U.S. Pat. No. 4,423,725, patented Jan. 3, 1984, describe a multiple surgical cuff alleged to have a variety of uses. PA0 Betancourt, U.S. Pat. No. 4,180,076, Dec. 25, 1979, describes a nasogastric catheter containing two inflatable vessels. PA0 German Offenlegungsschrift 28 34 956 and Russian Patents 651817 and 511951 describe the use of double balloon catheters for use in isolating the liver for the purpose of blocking blood flow from the liver. The catheters are provided with a bypass to allow blood flow to continue through the vein. Russian patent 511951 describes the use of a perforated wall catheter for removing blood from the liver and isolating it via a pump, and with respect to the perfusion of the liver with medicants and coolants, the perfusate is collected and returned to the liver via a pump.
1. We are able to use a high anti-cancer dosage which cannot be achieved by other methods, for example, intermittent or continuous intraarterial infusion. PA1 2. The administration of the anti-cancer agents is performed via both the hepatic artery and the portal vein. PA1 3. A combination with hyperthermia is given. PA1 perfusing at an anti-cancer agent to a tumor, PA1 collecting and containing the contaminated blood emanating from the tumor without general circulation of the contaminated blood to the body, PA1 transporting the contaminated blood from the body to an extracorporeal treatment system, PA1 removing anti-cancer agent from the blood in the extracorporeal treatment system, and PA1 returning the treated blood to the body. PA1 a. exposing a tumor in a body organ to one or more anti-cancer agents in higher than usual concentrations, PA1 b. removing from the organ effluent blood contaminated with the agent provided to the organ, without systemic exposure to the body, PA1 c. passing the effluent blood from tributary veins in the organ into a larger vein in which has been provided a catheter containing PA1 d. transporting the contaminated effluent blood through the catheter and thence from the body into an extracorporeal circuit, PA1 e. detoxifying the blood in the extracorporeal circuit, and PA1 f. returning the detoxified blood to the body. PA1 a. exposing a tumor in a body organ to one or more anti-cancer agents such as antineoplastic drug and biological response modifiers in higher than usual concentrations, PA1 b. removing from the organ effluent blood contaminated with the agent provided to the organ, without systemic exposure to the body, PA1 c. passing the effluent blood from tributary veins in the organ into a larger vein in which has been provided a catheter containing PA1 d. transporting the contaminated effluent blood through the catheter and thence from the body into an extracorporeal circuit, PA1 e. detoxifying the blood in the extracorporeal circuit, and PA1 f. returning the detoxified blood to the body. PA1 a. being percutaneously inserted into the inferior vena cava, PA1 b. closing off the flow of contaminated blood from the hepatic veins, and PA1 c. recovering the contaminated blood from the hepatic veins.